Research

Regulatory T cells (Treg) are a specialized subset of T cells that play a critical role in suppression of over-exuberant immune response and maintenance of immune system homeostasis. Abnormal Treg function has been linked to multiple autoimmune diseases, such as arthritis, type-1 diabetes, lupus, and multiple sclerosis, as well as inefficient tumor immunity.

Research in my lab is focused on the molecular and cellular mechanisms of regulatory T cell development and function. Using chromatin immunoprecipitation (ChIP) coupled with whole genome tiling array, we mapped ~700 genes that are directly regulated by Foxp3, a member of the forkhead transcription factor family that is expressed specifically in regulatory T cells. It plays a pivotal role in Treg development and function, while mutations of Foxp3 in human and mice lead to deficiency of regulatory T cells and fatal autoimmune disease.

Among the Foxp3 direct targets, there is a small group of transcription factors that potentially facilitate Foxp3 dependent suppressor programs in a modular fashion. For instance, IRF4 is required for suppression of Th2 immune response associated with asthma and allergy, and STAT3 is indispensible for suppression of Th17 response associated with inflammatory bowel disease (IBD). Our current goal is to further elucidate the Foxp3 transcriptional network, and shed more light on the molecular mechanisms of regulatory T cell suppressor function.

Since Foxp3 is the defining factor for regulatory T cells, the mechanism that regulates the induction and maintenance of Foxp3 expression also determines the development and stability of Treg cell lineage. To this end, we used a bottom-up approach to study pathways that regulate Foxp3 expression. By comparing Foxp3 genomic sequences among different species, we identified three conserved non-coding sequences (CNS) in the intronic region of the Foxp3 gene. Mice harboring deletion of individual CNS were generated to study the functions of these CNS regions in vivo. We showed each CNS has a distinct non-redundant function in Treg fate determination. Following up the initial characterization, we will further dissect the upstream pathways that control the expression of Foxp3 and regulatory T cell homeostasis.

The long-term goal of my lab is to search for novel ways to enhance or attenuate Treg activity, and to apply our findings in treatment of autoimmune diseases, improvement of organ transplant survival, and augmentation of anti-tumor immunity.

"Regulatory T cells play a key role in the immune system to
limit excessive immune reactions and prevent autoimmune
diseases. Research in my lab is focused on the underlying
molecular mechanisms that are involved in regulatory T cell
differentiation and their immune suppression function."

The immune system is a powerful doubleedged
sword. On one hand, it is armed to
fight a wide range of invading foreign pathogens.
On the other hand, if left unchecked,
it can also attack an organism's own tissues
and cause autoimmune diseases, such as
type 1 diabetes, multiple sclerosis and
rheumatoid arthritis. There are multiple
safeguard mechanisms built into our immune
system to prevent an autoimmune reaction.
A subset of T cells, named regulatory T cells
(Tregs), plays a key role in maintaining immune
homeostasis.

Abnormal Treg function has been linked to
a number of autoimmune diseases. Recent
studies showed that a protein known as Foxp3
is a pivotal regulator for Treg differentiation
and function. Mutations of Foxp3 in humans
and mice lead to a deficiency of regulatory T
cells and fatal autoimmune disease. Zheng's
lab is interested in mapping both the upstream
pathways that turn on Foxp3 expression
and the downstream genes that Foxp3
regulates. Zheng and his colleagues identified
several genes in the area of DNA that codes
for Foxp3 and are found in a number of
mammalian species. These genes appear to
be involved in controlling and maintaining
Foxp3 activity and in regulating the development
and stability of regulatory T cell lineage.
Using genomic approaches, the researchers
were able to map all Foxp3 downstream
target genes. They showed that among all
Foxp3 targets, a small group of proteins is
implicated in Treg-mediated suppression of
different subtypes of autoimmune responses.

Zheng and his team are now further exploring
the Foxp3 transcriptional network in regulatory
T cells and searching for key molecules
involved in the Treg suppression function.
Since manipulations of Tregs can either
weaken or strengthen the immune response,
their findings can potentially open new
avenues in the treatment of autoimmune
diseases, improve organ transplant survival
and enhance anti-tumor immunity."